This Research Project requests support for a 3 phase study of genetic influences on nicotine dependence, and their relationship to psychiatric cofactors and to genetically determined differences in initial sensitivity to nicotine. We will ascertain from Missouri state records and trace a target sample of 1600 female like-sex and 1600 male like-sex MZ and DZ pairs born 1950-74. One twin from each pair will receive a brief screening interview, to identify pairs where at least one twin has smoked 100 or more cigarettes (phase 1), A diagnostic follow-up interview will be conducted with both twins from pairs who are either concordant for or discordant for lifetime smoking. Assessments will include history of nicotine dependence (DSM-IV nd Fagerstrom), alcohol dependence, major depression, conduct disorder, and attention deficit hyperactivity disorder (phase 2). Genetic analyses of these data are expected to confirm (i) a substantial genetic influence on risk of nicotine dependence among those who become regular smokers and; (ii) significant genetic covariance between nicotine dependence and other psychopathology. In phase 3 we will assess the response to nicotine challenge of twins (both MZ and DZ) who have never smoked regularly from 3 groups: (a) both twins from pairs concordant for never having smoked regularly; (b) non-smoking twins only from pairs discordant for regular smoking where the smoker has a history of nicotine dependence (scored in upper 75%-ile on the Fagerstrom); and (c) non-smoking twins only from smoking discordant pairs where the smoker scored in the lower 75%-ile on the Fagerstrom. At baseline and after placebo or nicotine dose we will assess (a) heart rate, blood pressure, and digit skin temperature; (b) subjective ratings of stimulant and sedative effects; (c) electrocortical measures including the spontaneous EG and event-related potentials in a forewarned reaction time task. Genetic analyses of these data are expected to confirm a strong genetic influence in differences in initial sensitivity to nicotine that is associated with genetic differences in risk of nicotine dependence, with high initial sensitivity to nicotine associated with increased risk of nicotine dependence, with high initial sensitivity to nicotine associated with increased risk of nicotine dependence in regular smokers.